An expandable chamber piston type internal combustion engine operating in an open thermodynamic cycle includes a combustion process having a constant volume (isochoric) phase followed by a constant temperature (isothermal) phase.

The present invention relates generally to internal combustion engines and more particularly to expandable chamber piston engines operating in an open thermodynamic cycle.
Automotive vehicle and engine manufacturers, fuel injection equipment suppliers and, indeed, society as a whole, share in the desire for efficient, effective transportation. The balance between combustion processes to produce power, and those processes which create pollution, is best addressed by enhancing the fundamental efficiency of the engine processes.
It is well known that the ideal Carnot Cycle, in which isothermal heat addition and rejection are combined with isentropic compression and expansion, is the most efficient engine cycle for any given upper and lower operating temperatures. However, the Carnot cycle is not practical for an expanding chamber piston engine due to the very high (over 50:1) compression ratio required to produce significant power. Nevertheless, a practical process which could make some use of the highly efficient Carnot process would be an advance in the art.
The most practical engine, and thus presently the most predominant, is the Otto cycle engine which includes a compression process of a fuel-air mixture followed by unregulated combustion. It is well known that for a given compression ratio the ideal Otto cycle is the most efficient expanding chamber piston engine since the Otto cycle combines high peak temperature with a practical average temperature of heat input. However, the high peak combustion temperature of an Otto engine can cause auto-ignition of a portion of the fuel-air mixture, resulting in engine noise and damage to the engine, as well as the creation of excess amounts of undesired NOx.
In the past, auto-ignition in Otto cycle engines was reduced by use of chemical additives to the fuel such as lead compounds (no longer permitted by law), manganese compounds (which cause spark plug deposits to build up, resulting in misfire), benzene (the use of which is presently being curtailed by legislative mandate) or fuel reformulations to prevent deleterious auto-ignition while meeting environmental goals. Auto-ignition can also be reduced by limiting the combustion temperature, either through use of a lower compression ratio (which reduces both power and efficiency), or by exhaust gas recirculation, lean-burn or stratified charge techniques, all of which cause power loss.
For general purpose road use, the engines of emission-constrained passenger cars are presently limited to useful compression of about 10:1. Above that limit the increased cost of the fuel control system and the additional cost of more platinum or rhodium for exhaust catalytic converters generally outweighs the benefit of higher compression ratios. A technology which would allow a practical Otto compression process to operate at compression ratios higher than 10:1 would be an advance in the art.
An improvement on the Otto cycle, as represented by a higher useful compression ratio, is an ideal Diesel cycle comprising isothermal heat addition and isochoric (constant volume) heat rejection combined with isentropic compression and expansion. This ideal Diesel cycle overcomes the fuel octane limit of the Otto cycle by utilizing air alone for the compression process and mixing the fuel with the process air as part of the combustion process. This allows use of a low octane-rated fuel, but requires cetane-rated fuel (enhanced auto-ignition). However, the isothermal process of the aforedescribed ideal Diesel cycle was found to be impractical, due to the extremely high compression ratio (50:1) required, and an alternate heat addition process (isobaric or constant pressure) was put into practice.
Another variation on the ideal Diesel cycle is the ideal limited pressure cycle including combined isochoric and isobaric heat addition, and isochoric heat rejection combined with isentropic compression and expansion. This combustion process allows an engine to be operated at moderate compression ratios (14:1 to 17:1 for large open chamber engines) as well as high compression ratios (20:1 to 25:1 for small displacement engines).
While Diesel-type engines are fuel efficient, due to their high compression ratio, they tend to be heavier and lower in power than an Otto engine of the same displacement. In addition, all direct injection engines of the Diesel type suffer from an ignition lag which reduces the control and effectiveness of the combustion process. One way to overcome this ignition lag is to preheat the fuel to 1,500xc2x0 R before injection. This produces hypergolic combustion upon injection, but is an impractical method due to the short service life of the injector nozzle.
Hybrid engine processes have been developed incorporating characteristics of both diesel and spark ignition engines but these have proven impractical for road use. Examples of these hybrid processes include the Texaco TCCS, the Ford PROCO, Ricardo, MAN-FM and the KHD-AD. All employ open chamber, direct injection spark ignition engines using stratified charge techniques to improve efficiency. These developmental engines suffer substantial power loss because of ignition lag, incomplete utilization of the process air and poor mixing of the fuel/air charge.
Because the limits of current technology are thus being reached, there exists a need for an internal combustion engine that will provide a better balance between power production, fuel efficiency, pollution creation and pollution control by use of a more practical combination of thermodynamic processes.
Basically, the present invention meets the foregoing requirements and constraints by utilizing a new combination of thermodynamic processes which limits maximum combustion temperatures, thereby enabling an internal combustion engine to operate at a higher compression ratio, a higher power output or a lower peak temperature with a given fuel.
Broadly, in accordance with one exemplary embodiment, the invention is practiced by controlling the fuel quantity and injection timing of a direct injection system in an internal combustion engine, so as to produce a combustion process consisting of a constant volume (isochoric) phase and a constant temperature (isothermal) phase. The limited temperature engine cycle so achieved allows the use of substantially higher compression ratios with a given fuel or with a given NOx emission limit, thereby providing a higher practical thermal efficiency than the standard lower compression ratio Otto cycle when measured by fuel/air analysis or by analyzing the test data of an actual engine.
In addition, the limited temperature cycle so achieved allows a higher power output and a lower NOx creation rate at a given compression ratio with a low quality fuel.
In accordance with another aspect of the invention, there is provided a new method of operating an expanding chamber internal combustion piston engine for providing limited temperature combustion. Such an engine includes at least one cylinder and an associated piston for forming a combustion chamber with the piston having a top dead center position; an operating cycle including an intake stroke, a compression stroke and an expansion stroke; and a fuel introduction system. The method of operating the engine pursuant to the invention comprises the steps of first forming a predetermined fuel/air mixture by introducing a predetermined fraction in one or more discrete quantities of the total fuel necessary for complete combustion of the process air. Next, the relatively lean fuel/air mixture so introduced is ignited when the piston is substantially at top dead center, this first phase of combustion thereby comprising a substantially isochoric or constant volume process. The fuel supplied for the isochoric process is an amount which will produce a greatly reduced temperature of the working fluid, as low as 3,300 degrees Rankine, or less, even at high compression ratios. Last, there is introduced, substantially at the beginning of the expansion stroke, a second fraction (in one or more discrete quantities) of the total fuel necessary for complete combustion. The combustion resulting from the introduction of the second fraction is a substantially isothermal process. The isothermal process occurs at a temperature which is significantly less than that attained in a comparable Otto cycle engine having the same or a substantially lower compression ratio. NOX emissions are thereby limited and such reduction is obtained at lower cost than existing systems.
Those skilled in the art will recognize that the method of the present invention makes use of the Otto process for the first phase of the heat input or combustion process and the Carnot process for the second phase of heat input or combustion process. Comparison of the operating cycle of the invention with the standard Otto cycle using ideal fuel/air analysis shows an unexpected benefit from the invention: the overall operating efficiency of an engine (with a given compression ratio) will be greater using the limited temperature cycle of the present invention than when using the Otto cycle, when high temperature losses are considered. This increase in efficiency at a given compression ratio is a benefit derived from reduced cycle temperature.
Another advantage of the present invention is that it allows an engine to be operated more efficiently (at a higher compression ratio) than is possible with present engines. The most readily available motor vehicle gasoline fuels have combustion quality ratings of about 90 octane, which generally limits many engines to a compression ratio of about 10:1 for public road use. Since octane rating is indirectly related to high combustion temperature (high operating temperatures require high octane fuel), and the invention reduces the operating temperature, it follows that the invention enables the use of a higher engine compression ratio with a commensurate gain in engine efficiency.
In sum, the method of the present invention allows a practical engine to make use of an ideal process: during the isothermal combustion process, heat energy is converted directly to work. The invention utilizes present engine design and materials and may be practiced by modifying existing internal combustion engines to incorporate the desired compression ratio and appropriate fuel introduction systems.

Internal combustion engine with limited temperature cycle


Massive bodies for rapidly and safely preparing highly converted solutions of chlorine dioxide are disclosed. These massive bodies when added to water produce more chlorine dioxide than when the equivalent weights of the ingredients in powder form are added to water. The solutions produced by the addition of massive bodies to water are also disclosed. The concentration of chlorine dioxide in the solution is such that the ratio of the concentration of chlorine dioxide to the sum of the concentrations of chlorine dioxide and chlorite anion is greater than 0.25:1 by weight.

Free molecular chlorine dioxide in solution is an effective agent for the control of microorganisms and biological film deposits. However, the most common way to produce such solutions of free chlorine dioxide is to use an expensive and complicated chemical generator (see for example U.S. Pat. No. 5,009,875).
British patent 608,068 teaches the use of organic acid anhydrides to convert chlorite anion to free chlorine dioxide at a generally neutral pH. The fire and explosion dangers that result from combining a strong oxidizing chemical, such as sodium chlorite, with an organic chemical are also well known. As a result of the low conversion ratio produced by the compositions of this British patent, and the dangers inherent in compositions combining sodium chlorite and organic chemicals, the compositions of this British patent have received little commercial interest.
Recently, a membrane type device containing powdered chlorine dioxide precursor chemicals that produces a solution of free molecular chlorine dioxide when the device is immersed in water was described, see WO 99/24356. While this membrane device is superior to the prior art methods of producing chlorine dioxide solutions, the device has some shortcomings. It is relatively expensive (due to the cost of the membrane and of assembly), and the rate of chlorine dioxide delivery can be too slow for certain applications. Also, the device may float on the surface of the water/solution (due to entrapped air or chlorine dioxide gas), and this can result in the loss of some chlorine dioxide to the gas phase. Finally, the preferred membranes are insoluble in water, and may need to be removed from the chlorine dioxide solution after the chlorine dioxide generating reactions are completed. Removal of the spent membrane from the chlorine dioxide solution may, at times, be considered inconvenient.
The prior art also describes attempts to produce chlorine dioxide solutions from solid mixtures, including solid compacts such as tablets and briquettes, which are comprised, of materials that will generate chlorine dioxide gas when contacted with liquid water.
U.S. Pat No. 2,071,094 discloses dry solid compositions, including briquettes, comprised of a soluble chlorite and an acidifying agent which when contacted with water produce a xe2x80x9cdeodorizing reactionxe2x80x9d as the dry composition begins to dissolve (see col. 1, lines 34-38 and col. 2, lines 24-27). Upon reading this patent, it is not clear what is produced when the composition comes into contact with water. The substance, chlorine dioxide, is never mentioned and the only time the word xe2x80x9csolutionxe2x80x9d is used it is with reference to an aqueous solution of sodium chlorite (see col. 1, line 58). Thus, it cannot be ascertained whether the inventor was attempting to, or indeed ever did obtain an aqueous solution of chlorine dioxide when his briquette was contacted with water.
U.S. Pat. No. 5,324,447 describes, inter alia, a tablet comprising a chlorine dioxide precursor (e.g., sodium chlorite) and an activator component (e.g., an organic acid anhydride) which are present in amounts effective to produce (contact) lens disinfecting amounts of chlorine dioxide in a liquid medium (see, col. 3, lines 10-16). The term disinfecting amount is defined as such amount as will reduce the microbial burden by one log order preferably in ten (10) minutes or less (see col. 4, lines 11-15). This amount represents very little free chlorine dioxide, as even as little as 2 ppm of free chlorine dioxide can result in a 6 log bacterial reduction in 15 minutes. The patent does not disclose the amount of chlorine dioxide that is generated when a tablet of the invention is dissolved in water. Thus, all of the examples utilize aqueous solutions of stabilized chlorine dioxide and not water to test the tablets.
U.S. Pat. No. 5,399,288 discloses a solid composition releasing chlorine dioxide immediately after dissolution in water (see col. 1, lines 5-7). The composition comprises a chlorite salt, an oxidizing chlorine releasing agent and a proton donor present in the ratio of 4:1:3 (see col. 1, lines 65-67). When the oxidizing chlorine-releasing agent is omitted from the composition, the final yield of chlorine dioxide obtained was 63% but after three days (see Example 5). Further, and importantly, this patent does not discuss the preparation of tablets (see col. 2, lines 19-21). Thus, it appears that only powdered mixtures of reactants are disclosed.
U.S. Pat. No. 5,719,100 discloses production of chlorine dioxide in an aqueous solution from a tablet comprising a composition of sodium chlorite and an acid activator wherein the composition requires a reaction-preventing barrier between the sodium chlorite, [i.e., a protective reactive coat is formed on the sodium chlorite before it is mixed with the acid activator (see col. 4, lines 61-63) and the acid activator such that the two active ingredients do not xe2x80x9cexplosively reactxe2x80x9d together prematurely (see col. 4, line 53), i.e., a stable composition is obtained (see col. 4, line 46 through col. 5, line 9).
The present invention provides an improved device in the form of a massive body for the production of chlorine dioxide solutions. This new device rapidly provides high yield solutions of chlorine dioxide and overcomes shortcomings of prior art solid compositions for producing such solutions.
This invention provides a massive body that rapidly produces a solution of chlorine dioxide when immersed in water. The invention also includes the solutions obtained when a massive body is immersed in water. As used herein the term xe2x80x9cmassive bodyxe2x80x9d means a solid shape, preferably a porous solid shape, comprising a mixture of granular particulate ingredients wherein the size of the particles comprising the ingredients is substantially smaller than the size of the massive body. Such massive bodies may be formed by a variety of means known in the art, such as tabletting, briqueting, extrusion, sintering, granulating and the like. The preferred method of forming such massive bodies is by compression, also known as tabletting. For reasons of convenience, hereinafter references to tablets and tabletting shall be understood to be representative of massive bodies made by any method.
The tablet is comprised of a source of chlorite anions such as an alkali or alkaline earth metal chlorite, preferably sodium chlorite and one or more dry solid acid sources. Examples of such dry solid acid sources include inorganic acid salts, such as sodium acid sulfate, potassium acid sulfate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate; salts comprising the anions of strong acids and cations of weak bases, such as aluminum chloride, aluminum nitrate, cerium nitrate, and iron sulfate; solid acids that can liberate protons into solution when contacted with water, for example a mixture of the acid ion exchanged form of molecular sieve ETS-10 (see U.S. Pat. No. 4,853,202) and sodium chloride; organic acids, such as citric acid and tartaric acid; and mixtures thereof. Preferably the solid acid source is a solid inorganic acid source, and most preferably is sodium bisulfate. Surprisingly, a very high conversion rate of the chlorite anion to chlorine dioxide is obtained by use of the tablets of the invention. Thus, when the equivalent weights of tablet ingredients in powdered form are added to the same volume of water as the corresponding tablet, a much larger amount of chlorine dioxide is produced by the tablet than from the powder. Reasonable variations in stirring rate and/or water temperature have little to no effect on this surprising phenomenon. Thus, the tablets of the invention have been observed rapidly to produce a highly converted solution of free molecular chlorine dioxide, meaning that the conversion ratio (chlorite anion to chlorine dioxide) is  greater than 0.25. The term, conversion ratio, when utilized herein means the calculated ratio of the free chlorine dioxide concentration in the product solution to the sum of free chlorine dioxide plus non-reacted chlorite ion concentrations in the product solution. Further, the chlorine dioxide solution is rapidly produced in a safe and controlled manner; and when the chlorine dioxide concentration so produced is at typical use levels (0.5-200 ppm by weight) in typical tap water, the solution will contain substantially no free chlorine or hypochlorite anion and will have a generally neutral pH (i.e., pH 5-9). By the term, rapidly produced, we mean that total chlorine dioxide production is obtained in less than about 8 hours, preferably in less than about 2 hours and most preferably in less than about 1 hour.
The tablets of the present invention may, if desired, contain optional additional ingredients, which may be useful, for example to assist in the tabletting process, to improve the physical or aesthetic characteristics of the produced tablets and to assist tablet solubilization and/or the yield of chlorine dioxide obtained. Such ingredients include but are not limited to fillers such as attapulgite clay and sodium chloride; tabletting and tablet die lubricants; stabilizers; dyes; anti-caking agents; desiccating filling agents such as calcium chloride and magnesium chloride; pore forming agents such as a swelling inorganic clay, e.g., Laponite clay available from Southern Clay Products, Inc.; a chlorine producing agent such as dichlorocyanuric acid and salts thereof such as the sodium salt (NaDCC); and a framework former that can react with one or more other constituents in the formulation to produce a low solubility porous framework structure in which the chlorine dioxide forming reactions may proceed. Effervescing agents such as sodium bicarbonate may be included in small amounts, but they can reduce the conversion of chlorite anion to chlorine dioxide by accelerating breakup and dissolution of the tablet.
In general the tablets of the invention are superior to the prior art membrane device, see e.g., WO 99/24356, for the following reasons:
Tablets are typically less costly than the membrane device because they can be manufactured at a high rate on commercially available equipment and do not require the expense of a membrane enclosure to function;
Tablets generally produce chlorine dioxide at a higher rate than membrane devices, since the tablet does not have a membrane to restrict the escape of chlorine dioxide into solution;
The membrane devices frequently float when they are added to water while the tablets of the invention sink in water so they lose little chlorine dioxide to the gas phase; and
In one preferred mode, the tablet of the invention is completely soluble in water so the need to remove residue from the product chlorine dioxide solution is avoided.
While not wishing to be bound by any theory of operation, we believe that the enhanced yield of chlorine dioxide which is obtained by the use of the tablets of the invention may be explained in the following way. The tablet device functions when water enters the pore space within a tablet and produces a concentrated, acidic solution of chlorite anion within the pore space. The acid and chlorite (and optional ingredients that may be present) react under these concentrated conditions in the pores of the tablet rapidly to produce chlorine dioxide which diffuses out of the tablet into the bulk solution.
For the tablets to function properly, it is believed important that the chemical reactions occur in concentrated solution within the pore structure. There is little or no chlorine dioxide formed when the equivalent tablet ingredients in powder form are rapidly dissolved in aqueous media.
The invention includes two general types of tablet devices. One type of device comprises tablets that are fully soluble in water, and the preferred formulation of such tablets comprises dried powdered technical grade sodium chlorite and a dried powdered acid source, preferably sodium bisulfate. Additional dried powdered ingredients such as magnesium chloride and NaDCCA may optionally be added to even further improve the yield and rate of production of the chlorine dioxide. The dried powdered ingredients are mixed and the resultant powdered mixture is compressed in a tablet die at a pressure sufficient to produce a substantially intact tablet, typically about 1000-10,000 lb/in2. The resultant tablets are stable during storage as long as they are protected from exposure to water (either liquid or vapor). The tablets rapidly produce a highly converted solution of free chlorine dioxide when immersed in water.
The second type of device comprises tablets, which are not fully soluble in water at a high rate. They are designed to have (or produce) a low solubility or slowly soluble porous framework structure in which the chlorine dioxide forming reactions may proceed to substantial completion prior to dissolution of the porous framework. Generally tablets of this second type convert a greater proportion of their chlorite anion precursor chemical to chlorine dioxide compared to the fully soluble tablets described above.
The preferred formulation for this second type of tablet device comprises dried powdered technical grade sodium chlorite, dried powdered sodium bisulfate and dried powdered calcium chloride. A dried powdered clay such as Laponite clay and dried powdered NaDCCA may optionally be added to even further improve the yield and rate of production of the chlorine dioxide. As with tablets of the first type, the dried powdered ingredients are mixed and the resultant powdered mixture is compressed in a tablet die at a pressure sufficient to produce a substantially intact tablet, typically about 1000-10,000 lb/in2. The resultant tablets are stable during storage as long as they are protected from exposure to water (either liquid or vapor). They rapidly produce a highly converted solution of free chlorine dioxide when immersed in water.
Tablets of this second type generally provide more efficient conversion of chlorite anion to chlorine dioxide compared to tablets of the first type. It is believed that this occurs because the low solubility porous framework provides a favorable environment for the chlorine dioxide forming reactions to proceed until substantial exhaustion of the reactants.
Chlorine dioxide formation in tablets of the second type of device is believed to occur substantially within the favorable environment of the pore space of the low solubility (or slowly soluble) porous framework. Since the favorable pore structure of this framework appears to remain substantially intact during this reaction time, substantially all of the chlorite anion has an opportunity to react and form chlorine dioxide under favorable conditions within the pores. This maximizes chlorite conversion to chlorine dioxide. In contrast, a device of the first type is being dissolved into the bulk solution at the same time that it is producing chlorine dioxide. Since it is believed that the reagents will only react at a practically useful rate under concentrated conditions (such as those that exist within the pores of the tablets), that fraction of the chlorite that dissolves into bulk solution prior to conversion to chlorine dioxide will substantially remain as chlorite and not be converted to chlorine dioxide under the generally dilute conditions of the bulk solution.
The low solubility porous framework of the preferred composition of the second type of tablet device comprises a low solubility salt such as calcium sulfate and may additionally include a clay such as Laponite clay. The calcium sulfate preferably is formed from the reaction between calcium cations e.g., from the calcium chloride constituent and sulfate anions derived from the sodium bisulfate constituent. Other sources of calcium cations such as calcium nitrate as well as other sources of sulfate anions such as magnesium sulfate may also be used. The preferred clay, Laponite clay, is insoluble as provided and it is a swelling clay which, we believe, enhances the pore structure of the porous framework by forming cracks and cavities as it swells. We have found that forming the calcium sulfate framework in-situ via chemical reaction is particularly advantageous and that chlorine dioxide yield from such tablets is significantly better (nominally 25% better) compared to tablets in which calcium sulfate is a constituent of the initial powder formulation. The presence of the clay in addition to the calcium sulfate provides only a small improvement over the use of calcium sulfate without the clay.
By low solubility or slowly soluble porous framework, we mean a porous solid structure, which remains substantially undissolved in the product solution during the period of chlorine dioxide production. It is not necessary that the porous framework remain wholly intact during the reaction time to form chlorine dioxide. One aspect of this invention includes tablets of the second type in which the tablet disintegrates into substantially insoluble (or slowly soluble) granules that release chlorine dioxide into solution. This is acceptable, we believe, because the size of the granules is still large relative to the size of the pores within the pore space of the granules, so the necessary concentrated reaction conditions exist within the pore space despite the breakdown of the framework into granules.
In tablet devices of both types, it is preferred that the powdered ingredients be dry prior to mixing and tabletting in order to minimize premature chemical interaction among the tablet ingredients. When utilized herein the term dry means that each ingredient typically contains less than about 1% H2O.
General Procedures for Making and Testing the Tablets of the Invention Tablet Formation
The individual chemical components of the tablet formulation are dried prior to use. The desired amount of each component is carefully weighed into a plastic vial. In the following examples, formulations are given on a weight percent basis. The vial containing all the components of the tablet formulation is shaken to mix the components thoroughly. The contents of the vial are emptied into an appropriately sized die (e.g., 13-mm diameter for 1 g tablet). The plunger is placed in the die and the contents are pressed into a pellet using a hydraulic laboratory press. The maximum force reading on the press gauge was 2000 pounds unless otherwise noted. This pressure on the tablet punch may be converted to pounds/in2 if the area of the face of the plunger in in2 is known (typically 0.206 in2 for a 1 g tablet). The resulting tablet is removed from the die and placed in a closed plastic vial until use (typically within 10 minutes).
Tablet Performance
The tablet is placed in a volumetric flask or container filled with a known amount of tap water. Chlorine dioxide evolution starts immediately as evidenced by bubbles and the appearance of a yellow color. The tablet is allowed to react until completion. Completion of the reaction depends, in part, on the tablet type and size. Typically the reaction time is 2 hours or less if a 1 g tablet is partially insoluble and 0.5 hr. if a 1 g tablet is completely soluble. When reaction is complete, the flask/container is shaken or stirred in order to mix the contents. Then the contents are analyzed. Typically, chlorine dioxide is measured by uv-vis spectrometry, using four wavelengths (the average value is reported). Chlorite and chlorine are measured by titration of typically 25 ml of chlorine dioxide solution using procedures equivalent to those found in the text, Standard Methods for the Examination of Water and Wastewater, 19th Edition (1995) pages 4-57 and 4-58. This text is published jointly by the American Public Health Association, The American Water Works Association and the Water Environment Federation. The publication office is American Public Health Association, Washington, D.C. 20005. Total oxidants are measured by titration using a Brinkmann Autotitration System, 716 DMS Titrino equipped with a massive platinum electrode (Brinkmann Part No. 6.0415.100). The method is an iodimetric titration in an acid medium based on the oxidation of iodide to iodine and its subsequent reaction with the titrant, sodium thiosulfate. The typical procedure was as follows. One hundred milliliters of chlorine dioxide solution and a stirring bar were placed in a beaker and 2 g of potassium iodide (Reagent Crystals) and 10 ml of a 1N solution of sulfuric acid (Mallinckrodt) were added with stirring. The resulting solution is titrated with 0.1N thiosulfate solution (Aldrich Chemical Co.). The endpoint is automatically determined by the Brinkmann Titrino software. This endpoint is used to calculate the concentration of total oxidants in the sample. The pH of the original chlorine dioxide solution is measured using a pH electrode either on the solution xe2x80x9cas isxe2x80x9d and/or diluted with sufficient water to give approximately a 10 ppm concentration of chlorine dioxide.
Results
In the examples below, the above procedures are followed unless otherwise specified. Formulations are given as weight percents of each component on a dry basis. Technical grade sodium chlorite was used. Typically the actual sodium chlorite content of technical grade sodium chlorite is approximately 80% and the remainder is approximately sodium chloride (8.5%), sodium carbonate (6.1%) and sodium sulfate (4.5%). Yields are calculated on two bases. The first is the wt % yield of chlorine dioxide based on the tablet weight, i.e., wt % yield=100xc3x97(wt ClO2/wt tablet). The second is the chemical yield based on sodium chlorite. In this case one must take into account that technical grade sodium chlorite is only 80% pure. Thus, chemical % yield=100xc3x97(moles ClO2 produced)/(moles of NaClO2 in tablet). The stoichiometry of the acid reaction of sodium chlorite to chlorine dioxide limits the yield to 80%.
Conversion ratio is calculated as (wt chlorine dioxide)/(wt chlorine dioxide+wt chlorite). If the chlorite content of the solution was not determined or is unknown, a xe2x80x9cminimum conversion ratioxe2x80x9d is calculated. This ratio is wtClO2/wt total oxidant. Total oxidant typically consists entirely of chlorine dioxide, chlorite and chlorine. The chlorine content of solutions from tablets is typically low, so this minimum conversion ratio is a reasonable approximation of the conversion ratio. Examples are illustrated below.

Massive bodies for producing highly converted solutions of chlorine dioxde


A separator card substrate material for use in high speed document processing machines is imprinted with an array of periodically laterally spaced magnetic strips across an area of the face of the substrate and furthermore a machine readable code array of light and dark blocks representing selected data is imprinted in at least a portion of the same space of the substrate as is occupied by the magnetic strips with the light and dark blocks spanning widthwise dimensions between the strips as well as lengthwise dimensions between the strips. The interleaving of the magnetic strips and the light and dark blocks enables the separator card to be encoded with relatively large fields of optical data enabling the use of low resolution sensors for detecting the optical data used to uniquely identify each separator card without interfering with the function of the magnetic strips.

1. Field of the Invention
This invention relates to separator cards usable with currency and other document processing, identification, sorting and counting machines.
2. Description of Related Art
High speed, continuous processing of paper of value (e.g. bank notes or currency) as well as checks and other documents using machines that scan the documents, recognize differences and discriminate between the documents, and count and sort the documents typically use a separator sheet between batches of documents to enable the machine to continuously process the different batches of documents without commingling the documents or data related to the documents. Such separator sheets, typically called separator cards, are interleaved between the separate batches of documents to be processed and contain machine readable indicia or codes that enable various sensors within the machine to recognize the separator card, read data on the card, and discriminate the separator card from the documents being processed.
High speed document processing machines of the type described above typically contain sensors and software that enable the machine to sense and identify various information or data associated with the documents as well as the separator cards. Such sensors, for example, include devices that measure physical properties of the documents (e.g., thickness sensors), optical character recognition systems, magnetic sensors for detecting magnetic coded information provided on or in the documents, bar code scanners and magnetic character reading systems.
It is highly desirable that the various batches of documents to be processed through such machines be maintained in discrete bundles or batches so that the data derived from each batch may be processed within the machine to provide reports reflecting various information desired concerning the respective batches of documents. For example, if the documents comprise currency, each batch of currency may comprise an individual account deposit that is to be counted, sorted and credited to an individual account without substantial human intervention. The processing of the currency, for example, may be carried out by a commercial bank, a central bank or within a private or public enterprise, such as a gambling casino or municipal transit authority. Separator cards are useful to enable the machine to discern the beginning and end of individual batches of documents and a description of such a system, including a separator card configuration is disclosed in U.S. Pat. No. 5,917,930 granted Jun. 29, 1999. Reference may be made to this patent for a further description of a representative application of separator cards in high speed currency processing machines.
In accordance with known principles, separator cards should be recognizable using various sensors already provided in the document processing equipment and furthermore, in the event of a misfeed resulting in both a separator card and a document being fed simultaneously through the machine sensors, it is desirable that the sensors will discern the presence of the separator card even though it may be covered by such document. Typically, this is a accomplished by using magnetic sensors to detect magnetic strips imprinted or otherwise provided on the separator card in a pattern or array that enables the sensors to recognize the presence of the separator card not withstanding the fact that it is covered by an opaque layer constituted of the misfed document.
The aforesaid U.S. Pat. No. 5,917,930 describes a prior art system for detecting a separator card in the event of a misfeed when a document (currency) covers a separator card during processing of separate batches of documents.
In addition to the magnetic strips, it is desirable to imprint separator cards with other machine readable codes or characters that represent useful data for machine processing of the documents and for discriminating the separator cards. At minimum, it is desirable to provide an imprinted numeric (or alpha-numeric) code on the separator cards that is unique to each card to enable the processing machine to identify a batch of documents that accompanies a separator card with associated data obtained from the documents among the respective batches of documents being processed. The specific separator card identifier may be imprinted in the form of a bar code, a set of characters that may be recognized by optical character recognition (OCR) equipment or magnetic character recognition systems. The separator card typically will be imprinted with other indicia indicating the orientation of the separator card as well as providing reference points that may be discerned by the various sensors of the document processing machine.
Modern document processing machines, particularly currency processing machines, operate at very high speeds with the result that various sensors used to detect, discriminate and recognize data contained in the documents must be capable of detecting and processing information extremely rapidly as well as extremely accurately. The need for high speed recognition of data, particularly optically captured data, requires very costly and sophisticated detection systems capable of providing input information to the processing software used in such machines with virtually negligible error rates. For this reason, such document processing machines tend to be costly and complex.
It is highly desirable to reduce the cost in complexity of document processing machines, particularly currency processing machines, and the present invention has as an objective the simplification of detecting and reading optically visible code information on separator cards of the type described above to thereby enable the use of less costly and less sensitive optical reading and code recognition devices to identify an individual separator card while still enabling high speed continuous processing of batches of documents separated by the separator cards that each having a unique card identifier imprinted thereon.
Generally, the larger the coded information imprinted on a document the easier it is to be detected by optical viewing and image capturing systems. Such large codes therefore are desirable to enable the use of simpler, less costly optical scanner systems, including lower resolution scanners. The problem arises, however, in that a separator card has limited space for imprinting large blocks of code thereon, particularly when a substantial portion of the separator card is imprinted or otherwise contains an extensive array of magnet strips used for detecting the separator card during high speed document processing.
Given that separator cards typically require imprinting on a single face thereof the unique card identifier (typically a multi-digit numerical sequence) and given that a bar code also must be imprinted on the same face of the separator card, a problem arises in finding a location on the card for a relatively large array of optically recognizable coded information that is machine readable during high speed processing of batches of documents and their respective separator cards. The present invention has as its objective a solution to such problem.
The present invention contemplates a separator card having an array of periodically laterally spaced magnetic strips imprinted thereon across a surface area of a separator card substrate that may be recognized and sensed by magnetic sensing device contained within a document processing machine. In addition, the invention contemplates using an array of relatively large light and dark blocks arranged in a machine readable code format wherein the blocks are disposed between and fully span the distance between the magnetic strips, as well as at least part of the distance lengthwise between the strips. Thus, the invention permits both the magnetic strips and the large block optical code array to be interleaved in a compact manner over the same area of a separator card. Because the array of light and dark blocks of optically recognizable data does not interfere with the underlying magnetic strips, separate sensors may be utilized to detect the magnetic strips and the blocks of code without interfering with any sensing of the respective magnetic and optical data.


An ophthalmic formulation is disclosed which reduces dilation in dim light and reduces redness.

The present invention relates to a composition formulated and administered to a human eye to reduce dilation and redness.
While it is known that pupil size varies in its diameter in darkness between individuals from 3 mm to 9 mm, little attention has been paid to the effect of this difference on the night vision and vision in dim light (scotopic vision is dark adapted vision). Those with large pupils suffer from much more light scatter, glare, halo, and related aberrant focus of light rays that can make function under certain conditions of lighting very difficult.
Laser vision correction in particular has added new quality of vision difficulties for many of these individuals. Exposing the retina to light focusing from as much as nine times more surface area essentially magnifies every variation in curvature from the ideal. Currently, only direct acting miotic agents such as pilocarpine are used in an effort to decrease pupil size.
Pilocarpine causes brow ache, ciliary muscle contraction and pseudo myopia, excessive dimness when first applied, and redness. Its effect lasts only a few hours, and it has known, though remote, risk of retinal detachment probably related to pull on the retina from stimulated ciliary muscle contraction. For these reasons it is rarely tolerated or considered a clinically useful alternative for patients with large pupils in dim light.
Another medication used to affect pupil size is dapiprazole, an alpha-1 adrenergic receptor blocking agent. Dapiprazole is 5,6,7,8-tetrahydro-3-[2-(4-o,tolyl-1-piperazinyl)ethyl]-8-triazolo[4,3-a]pyridine hydrochloride. It is available in a 0.5% solution to partially counteract, or reverse, the dilation effect of phenylephrine, an adrenergic dilating agent, and the dilating and accommodation loss caused by tropicamide. In addition to producing redness upon instillation, dapiprazole has very little effect on pupil size in dim light in clinical application when used topically for this purpose, and therefore its sole use is as a treatment of iatrogenically induced mydriasis produced by adrenergic or parasympatholytic agents.
An ophthalmic formulation of the invention preferably obtains two simultaneous effects (a) reducing the amount of dilation the eye would normally undergo in a low light environment; and (b) reducing eye redness. Reducing normal dilation can be obtained by administering a compound which interferes with the normal stimulation of muscles which cause dilation. This can be done, for example, with an alpha 1 antagonist. However, redness may be reduced using an alpha 1 agonist. The antagonist and agonist will, in general, counteract each other. The present invention provides a particularly preferred formulation of (a) an alpha 1 antagonist which is phentolamine; and (b) an alpha 1 agonist which is tetrahydrozoline and specifically tetrahydrozoline hcl. This combination reduces dilation and redness.
A formulation for optimizing pupil size in extreme lighting conditions is disclosed. The formulation is preferably a solution of the type used in an artificial tear formulation having dissolved therein a therapeutically effective amount of a compound characterized by its ability to reduce dilation of the eye, particularly in dim light. The compound generally interferes with a natural biochemical reaction which results in the stimulation of the dilator muscles of the eye. The formulation is preferably further comprised of a compound which reduces eye redness, e.g. tetrahydrazolene. The compound which has the ability to disrupt endogenous compounds which stimulate dilator muscles of the eye may be an alpha 1 antagonist which belongs to a class of compounds with phentolamine or phenoxybenzamine groups.
A method of optimizing pupil diameter is disclosed wherein the pupil diameter in dim light is effected so that it is not more than 200% greater than its size in bright light. The method encompasses administering a therapeutically effective amount of an alpha 1 antagonist to an eye of a person in need thereof. The optimized pupil diameter in dim light may be no more than 5 mm, and the pupil diameter in bright light may be constricted no more than 1 mm. Further, the optimized pupil diameter in dim light may be between and including 3 mm and 5 mm and will vary with different patients. Actual results with human patient""s are shown in the Examples.
In accordance with the method of the invention an application device such an eyedropper is utilized in order to apply a therapeutically effective amount of an alpha 1 agonist to the eye of a patient which is preferably the eye of a human patient. Thereafter, the formulation is allowed to effect the pupil of the eye and contract the pupil so that the pupil does not expand above a level which is twice the level of dilation when the eye of the patient is present in bright light. Accordingly, another aspect of the invention is a formulation comprised of an aqueous solution having an alpha 1 agonist present therein wherein the formulation is present in an eyedropper.
The present invention is also directed to a method for optimizing pupil diameter in dim light by minimizing its dilatation in response to less light, comprising administering a therapeutically effective amount of an alpha 1 antagonist to an eye of a person in need thereof. In this method, dilatation of the pupil diameter in dim light may be minimized in response to less light compared with bright light, and the method may not induce ciliary muscle contraction.
In the method of the present invention, the patient may suffer from excessively large pupils in dim light, and the patient may suffer from poor quality of vision, and the patient may be undergoing medication that results in dilatation of the pupil diameter. Alternatively, the pupil diameter of the patient may be naturally excessively dilated as a result of response to dimming of light.
The method of the invention may be carried out by directly instilling onto the eye an eye drop formulation of the invention. Optionally, the alpha 1 antagonist may be administered by contacting a contact lens, and the contact lens applied to the eye. In the method of the invention, the used alpha 1 antagonist preferably may belong to a class of compounds belonging to the phentolamine or phenoxybenzamine groups.
The present invention is directed to a method for reducing pupil diameter in dim light in cases where dilation of the pupil is excessive, such as 6 mm or greater. Administering a formulation of the invention does not induce ciliary contraction or undesirable pseudomyopia that may result from taking certain medication. Formulations disclosed here reverse mydriasis of parasympatholytic agents. Formulations of the invention are effective on agents paralyzing accommodation such as 1% cylogyl, which can then be used for more complete cycloplegia and accurate prelaser refractive measurement.
There are no generally available eye drops for optimizing pupil size such as by reducing pupil diameter in dim light without undesirable side effects. The present invention recognizes that the alpha-1 antagonists which are currently used for treatment of high blood pressure, treatment of pheochromocytoma, migraines, bladder spasm, prostate enlargement, and sexual dysfunction can be formulated used in reducing pupil diameter.
The present invention provides an ophthalmic. composition which achieves the combined requirements of comfort and pupil diameter optimization.
Alpha adrenergic receptor antagonists function to block alpha-1 receptor mediated contraction of arterial and venous smooth muscle. Alpha-2 adrenergic receptors are involved in suppressing sympathetic output, increasing vagal tone, facilitating platelet aggregation, inhibiting the release of norepinephrine and regulating metabolic effects. Alpha adrenergic antagonists have a wide spectrum of pharmacological specificities and are chemically heterogeneous.
Alkylating agents, imidazolines, piperazinyl quinazolines and indoles comprise. the various chemical classes of alpha receptor antagonists. Many have both alpha-1 and alpha-2 receptor antagonist activity. For the present invention alpha-2 activity as represented by the indoles is of no clinical benefit. The alkylating agents offer potential for long term effectiveness for minimizing pupillary dilation, but are less effective and cause more redness than the imidazolines, such as phentolamine. The piperazinyl quinazolines, such as prazosin and dapiprazole, have a modest effect on pupil diameter in dim light, but to date our research shows they are not as clinically effective as the imidazolines for this purpose. Development of longer lasting, more potent piperazinyl quinazolines may be clinically effective however. As phentolamine is not as strong an alpha-1 receptor antagonist as prazosin its stronger clinical benefit may relate to other related properties of the drug as well as its alpha-1 antagonism. These properties include blocking receptors for 5-HT, release of histamine from mast cells, and blockage of K+ channels. Phenoxybenzamine is similar in its chemical mediation.
An aspect of the invention is an ophthalmic formulation comprised of an aqueous solvent and an alpha 1 antagonist. The aqueous solvent may, in its simplest form, be water but is preferably a solvent comprised of an ophthalmic artificial tear solution. The alpha 1 antagonist is preferably present in a relatively low concentration e.g. less than 1% concentration. For example, the alpha 1 antagonist may be present in an amount in the range of 0.01 milligram per cubic centimeter of aqueous solvent to about 50 milligram per cubic centimeter of solvent. Another aspect of the invention is the formulation of the invention present within an application device such as a conventional or improved eyedropper of the type described herein.
An advantage of the invention is that it can be utilized to treat patients who have been subjected to laser surgery and have developed a range of different vision problems as a result of excessive dilation of their pupils.
A feature of the invention is that the alpha 1 antagonist can be formulated in a manner which is readily administered to the eye to obtain a desired effect.
These and other aspects, advantages and features of the invention will become apparent to those skilled in the art upon reading this disclosure.
Before the present formulations and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas or steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.
It must be noted that as used herein and in the appended claims, the singular forms xe2x80x9caxe2x80x9d, xe2x80x9candxe2x80x9d, and xe2x80x9cthexe2x80x9d include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to xe2x80x9ca compoundxe2x80x9d includes a plurality of such compounds and reference to xe2x80x9cthe stepxe2x80x9d includes reference to one or more step and equivalents thereof known to those skilled in the art, and so forth.
The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
It is well known that pupillary dilation in dim light is a teleologic adaption to allow more light to enter our eyes. Along with adaptions on the retina to scotopic, or night vision, this allows increased useful acuity over a very large range of lighting in low lit situations. Less well known is the dramatic range that exists among human beings of the degree to which pupils will dilate in dim light, ranging from maximal dilation in complete darkness of as little as 3 mm in some individuals to as high as 9 mm in others. This difference is part of the genetic makeup of an individual.
When living in literal total darkness there may have been a very slight advantage to having larger pupil diameters in dim light, but whatever advantage was conferred has been lost once several advances in civilization resulted in illumination; including artificial means of background lighting, neon lights. to allow signs to be more easily read, fluorescent light with its weighted blue more highly scattering component, and point sources of light caused by car headlights and traffic lights. These light sources are visible at optimal quality when sufficient corneal diameter exists to allow light to enter, such as a 3 mm pupil, but less corneal diameter is used to refract light, as less light scatter is induced than 5-6 millimeters pupils or larger. The preferred optimized pupil size in dim light according to the present invention is about 3-5 millimeters, more preferably 4-5 millimeters.
The peripheral corneal curvature in many people is not in perfect curvature alignment with that of the central cornea. In individuals with small to moderate pupils in dim light the pupil acts as a filter so that the peripheral cornea in these cases is not a factor. But, for larger pupils in dim light, peripheral corneas may be either too steep or too flat in many cases relative to the central curvature, causing spherical aberration. These corneas are technically referred to as either prolate or oblate when imperfect. The eye drops of the present invention clinically eliminate virtually all such spherical aberration, as the peripheral corneal curvature outside of a central 4-5 mm optical zone are filtered by the treated smaller pupil in dim light and the extraneous light focused by the spherical aberration is eliminated.
Three millimeter pupils are sufficiently large to allow sufficient light to enter the eye in scotopic situations, yet provide excellent filters to minimize light scatter of ambient artificial light and or point sources of light. Nine millimeter pupils on the other hand, utilizing nine times more corneal surface area, induce considerable light scatter of point sources, neon lights, and fluorescent blue light. While the current state of the art within the ophthalmic and optometric professions does not generally recognize this distinction, and wherein refractive surgery standard of care does not generally recognize a distinction in pupil diameter in, dim light as a predictive factor in outcome, use of the novel pharmacologic method of the present invention has demonstrated this to be so in clinical use. Tables 1 and 2 demonstrate the results of a study of several different alpha adrenergic antagonists on several patients, with different parameter being measured.
Refractive optical aids such as glasses or contact lenses increase the degree of light scatter in scotopic situations by adding optical elements that are imperfect in that they have surfaces that scatter light. Refractive surgery on the cornea, whereby a change in contour is induced by surgical means that can include incision (RK), laser ablation (Lasik, PRK), or prosthesis (plastic segments inserted into the cornea) also adds imperfections that increase the degree of light scatter in scotopic conditions. The variables of pupil size in dim light and refractive optics adding to light scatter has created circumstances in which individuals have quality of vision difficulty navigating in scotopic situations as a result of glare, halo, and related distortions at night or in dimly lit environments of any kind.
The invention is particularly useful in treating patients who have been subjected to various types of refractive surgery as described above. Because such surgery can increase the degree of light scatter the administration of the formulation of the invention can modulate this effect by contracting the pupil. Thus, the invention includes carrying out refractive surgery on a patient and thereafter administering a formulation of the invention to the patient over time as needed e.g. to maintain the pupil size at about 3-5mm, preferably 4-5mm. The formulation of the invention may be administered periodically on a daily basis (twice daily or as needed) and particularly administered in situations where the patient is subjected to dim light.
The term xe2x80x9cdim lightxe2x80x9d is used herein to refer to a light environment wherein the pupils of the patient are dilated to a substantially maximum amount. Alternatively, the term xe2x80x9cbright lightxe2x80x9d is used herein to describe a surrounding light environment wherein the pupil of the patient""s eye is contracted maximally i.e. dilated to a minimum amount. An aspect of the present invention is that the formulation can reduce the differential in pupil dilation and in particular reduce the dilation of the patient""s pupil to an amount of 200% or less in dim light as compared to the amount of dilation which would occur in bright light.
The method of the invention utilizes a novel pharmacologic means of optimizing pupil size by reducing pupil size in dim light. Conventional teaching of eye specialists has been to use constricting agents of the pupil, such as acetylcholine or cholinesterase inhibitors to reduce pupil size. Using dilute concentrations of such agents it is possible to constrict the pupil and create improved viewing for affected individuals in scotopic environments. However, undesirable side effects of such medications, including excessive constriction initially causing severe dimming, brow ache, generalized pain, redness, and induced blurring secondary to ciliary accommodation, severely limits the value of these classes of pharmacologic agents. Retinal detachment is a known rare complication of its use.
The pharmacologic method of the present invention utilizes a class of compounds known as alpha 1 antagonists to inhibit pupillary dilation in scotopic conditions preferentially over constriction of the pupil, affecting the dilator muscles of the iris preferentially, and has no clinically significant effect on the ciliary muscle responsible for accommodation. This class of compounds has been used to treat hypertension, prevent bladder spasmodic contractions and improve urinary outflow, and treat prostate enlargement. While toxic levels of alpha 1 antagonists are known to cause pinpoint pupils, no formulation has previously been developed as a topical pharmaceutical agent to limit dilation of the iris.
A significant feature of the present invention is to employ more potent alpha antagonists, particularly alpha 1 antagonists, to allow improvement in quality of vision in dim light without negative clinical effects in normal lighting conditions. Additionally, another feature of the present invention is to reverse the effects of parasympatholytics more effectively than dapiprazole.
The composition-of the present invention can be used to optimize pupil size to obtain enhanced vision acuity in dim light by reducing the pupil diameter in dim light, but which does not clinically substantially reduce the pupil size in bright light, when the pupil size does not require it to be treated to reduce the pupil size to the same extent as the pupil under dim light.
According to the invention, the optimized pupil diameter in dim light is no more than 200% greater than that in bright light. Preferably, the pupil diameter in dim light is no more than 150%, more preferably, 100%, even more preferably, 75%, still more preferably, 60%, still more preferably, 50%, and most preferably, 33% greater than that in bright light.
While the composition of the present invention can be used to optimize pupil size under any circumstances, the composition of the invention is administered to the eye of an individual to reduce naturally occurring pupillary dilation in dim light, especially in situations where the dilation is excessive to affect vision acuity. The composition of the invention can be used also to counteract pupil dilatation caused by medication.
As used in the present application, alpha 1 antagonist refers to any agent that binds to the alpha 1 adrenergic receptor, which includes alpha 1 adrenergic receptor antagonist. Preferably, the alpha 1 adrenergic receptor is iris smooth muscle dilator selective. More preferably, the alpha 1 antagonist is in the phentolamine family, known as imidazolines, an alkylating agent such as phenoxybenzamine, or a piperazinyl quinazoline with more potent alpha-1 adrenergic antagonist activity than dapiprazole. Most preferably, the alpha 1 antagonist of the invention is phentolamine or phenoxybenzamine, but any alpha 1 antagonist can be used in the present invention.
Alpha 1 antagonists such as phentolamine or phenoxybenzamine. These compounds are currently used to treat pheochromocytoma, a condition in which alpha receptor stimulants such as epinephrine and norepinephrine are released throughout the body in extremely high concentration.
Examples of alpha 1 antagonist are disclosed within issued U.S. Pat. No. 6,046,207 issued Apr. 4, 2000. Other examples are disclosed within U.S. Pat. Nos. 5,891,882 and 5,792,767. The above cited three U.S. patents are incorporated herein by reference to disclose alpha 1 antagonist. Further, publications cited in these patents are incorporated herein by reference in order to disclose and describe therapeutically effective compounds which can be formulated and used in connection with the present invention when used in appropriate. ophthalmic formulations and applied directly to the eye of a patient to effect pupil dilation.
According to the invention, an ophthalmic composition containing an alpha 1 antagonist is advantageously applied topically to the eye, especially in the form of a solution, a suspension, an ointment, a gel or a solid insert. Such compositions comprise the active ingredient, for example, in a range of from approximately 0.01 milligrams per cc to approximately 50 milligrams per cc, preferably from approximately 0.05 milligrams per cc to approximately 20 milligrams per cc, or more preferably in the range of from approximately 0.1 milligrams per cc to approximately 10 milligrams per cc and most preferably in the range of from 1 milligram per cc to 5 milligrams per cc. The dose of the active ingredient may depend on various factors, such as mode of administration, requirement, age and/or individual condition.
A preferred concentration of 3.3 milligrams per cc is administered by placing a single drop on a moist soft contact lens, and inserting the lens for 15-45 minutes, 1xc3x97 per day. Administered in this manner the drop has a 20-24 hour clinical effectiveness, and in fact appears to have cumulative affect, such that with regular usage an every other day administration via the contact lens may be all that is necessary for some patients. The contact lens dosing allows for preferential absorption within the cornea, maximizing drop utilization and minimizing mild redness that may otherwise occur as well as the remote risk of systemic absorption. The amount of phentolamine within 1 dropxe2x80x94less than 0.33 mgxe2x80x94is about 15 xc3x97 less than the clinically recommended dosing for testing within the body. Of this it is unlikely as much as 10% would ever reach the systemic circulation, resulting in 150xc3x97 less than a typical clinical dosage. Using contact lens dosing this is estimated to be""still 10xc3x97 less, or 1500 times less than a typical clinical dosage. The drop may be administered in a 3.3 milligram per cc concentration directly to the eye as a recommended daily or BID dosing.
An effective drop for the purpose of the present invention, because it limits pupil dilation and does not significantly affect pupillary constriction should have significantly more effect and cause significantly increased percentage reduction in pupil diameter in patients with large pupils in dim light, whose dim light pupil exceeds their daylight pupil considerably, and much less effect on pupil diameter in patients who have a more idealized pupil diameter in dim light, where their dim light pupil is nearly equal to their daylight pupil. This is in fact the case with phentolamine as administered (see Table 2).
There are used for a corresponding ophthalmic composition customary pharmaceutically acceptable excipients and additives known to the person skilled in the art, for example those of the type mentioned below, especially carriers, stabilizers, solubilizers, tonicity enhancing agents, buffer substances, preservatives, thickeners, complexing agents and other excipients. Examples of such additives and excipients can be found in U.S. Pat. Nos. 5,891,913, 5,134,124 and 4,906,613. Such compositions are prepared in a manner known, for example by mixing the active ingredient with the corresponding excipients and/or additives to form corresponding ophthalmic compositions. The active ingredient is preferably administered in the form of eye drops, the active ingredient being conventionally dissolved, for example, in a carrier. The solution is, where appropriate, adjusted and/or buffered to the desired pH and, where appropriate, a stabilizer, a solubilizer or a tonicity enhancing agent is added. Where appropriate, preservatives and/or other excipients are added to an ophthalmic composition.
Carriers used in accordance to the present invention are typically suitable for topical or general administration, and are for example water, mixtures of water and water-miscible solvents, such as C1- to C7-alkanols, vegetable oils or mineral oils comprising from 0.5 to 5% by weight hydroxyethylcellulose, ethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone and other non-toxic water-soluble polymers for ophthalmic uses, such as, for example, cellulose derivatives, such as methylcellulose, alkali metal salts of carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylhydroxypropylcellulose and hydroxypropylcellulose, acrylates or methacrylates, such as salts of polyacrylic acid or ethyl acrylate, polyacrylamides, natural products, such as gelatin, alginates, pectins, tragacanth, karaya gum, xanthan gum, carrageenin, agar and acacia, starch-derivatives, such as starch acetate and hydroxypropyl starch, and also other synthetic products, such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide, preferably cross-linked polyacrylic acid, such as neutral Carbopol, or mixtures of those polymers. Preferred carriers are water, cellulose derivatives, such as methylcellulose, alkali metal salts of carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylhydroxypropylcellulose and hydroxypropylcellulose, neutral Carbopol, or mixtures thereof The concentration of the carrier is, for example, from 1 to 100,000 times the concentration of the active ingredient.
The solubilizers used for an ophthalmic composition of the present invention are, for example, tyloxapol, fatty acid glycerol poly-lower alkylene glycol esters, fatty acid poly-lower alkylene glycol esters, polyethylene glycols, glycerol ethers vitamin E and vitamin E derivatives, such as Vitamin E Tocopherol Polyethylene-.Glycol 1000 Succinate (TPGS) or mixtures of those compounds. A specific example of an especially preferred solubilizer is a reaction product of castor oil and ethylene oxide. Reaction products of castor oil and ethylene oxide have proved to be particularly good solubilizers that are tolerated extremely well by the eye. Another preferred solubilizer is tyloxapol. The concentration used depends especially on the concentration of the active ingredient. The amount added is typically sufficient to solubilize the active ingredient. For example, the concentration of the solubilizer is from 0.1 to 5000 times the concentration of the active ingredient.
According to the present invention lower alkylene means linear or branched alkylene with up to and including 7 C-atoms. Examples are methylene, ethylene, 1 ,3-propylene, 1,2-propylene, 1,5-pentylene, 2,5-hexylene or 1,7-heptylene. Lower alkylene is preferably linear or branched alkylene with up to and including 4 C-atoms.
Examples of buffer substances are acetate, ascorbate, borate, hydrogen carbonate/carbonate, citrate, gluconate, lactate, phosphate, propionate, perborate and TRIS (tromethamine) buffers. Tromethamine and borate buffer are preferred buffers. The amount of buffer substance added is, for example, that necessary to ensure and maintain a physiologically tolerable pH range. The pH range is typically in the range of from 5 to 9, preferably from 6 to 8.2 and more preferably from 6.8 to 8.1.
Tonicity enhancing agents are, for example, ionic compounds, such as alkali metal or alkaline earth metal halides, such as, for example, CaCl2, KBr, KCl, LiCl, Nal, NaBr or NaCl, or boric acid. Non-ionic tonicity enhancing agents are, for example, urea, glycerol, sorbitol, mannitol, propylene glycol, or dextrose. For example, sufficient tonicity enhancing agent is added to impart to the ready-for-use ophthalmic composition an osmolality of approximately from 50 to 1000 mOsmol, preferred from 100 to 400 mOsmol, more preferred from 200 to 400 mOsmol and even more preferred from 280 to 350 mOsmol.
Examples of preservatives are quaternary ammonium salts, such as cetrimide, benzalkonium chloride or benzoxonium chloride, alkyl-mercury salts of thiosalicylic acid. such as, for example, thiomersal, phenylmercuric nitrate, phenylmercuric acetate or phenylmercuric borate, parabens, such as, for example, methylparaben or propylparaben, alcohols, such as, for example, chlorobutanol, benzyl alcohol or phenyl ethanol, guanidine derivatives, such as, for example, chlorohexidine or polyhexamethylene biguanide, or sorbic acid. Preferred preservatives are cetrimide, benzalkonium chloride, benzoxonium chloride and parabens. Where appropriate, a sufficient amount of preservative is added to the ophthalmic composition to ensure protection against secondary contaminations during use caused by bacteria and fungi.
The ophthalmic compositions may comprise further non-toxic excipients, such as, for example, emulsifiers, wetting-agents or fillers, such as, for example, the polyethylene glycols designated 200, 300, 400 and 600, or Carbowax designated 1000, 1500, 4000, 6000 and 10,000. Other excipients that may be used if desired are listed below but they are not intended to limit in any way the scope of the possible excipients. They are especially complexing agents, such as disodium-EDTA or EDTA, antioxidants, such as ascorbic acid, acetylcysteine, cysteine, sodium hydrogen sulfite, butyl-hydroxyanisole, butyl-hydroxytoluene or alpha.-tocopherol acetate; stabilizers, such as a cyclodextrin, thiourea, thiosorbitol, sodium dioctyl sulfosuccinate or monothioglycerol vitamin E and vitamin E derivatives, such as Vitamin E Tocopherol Polyethylene Glycol 1000 Succinate (TPGS); or other excipients, such as, for example, lauric acid sorbitol ester, triethanol amine oleate or palmitic acid ester. Preferred excipients are complexing agents, such as disodium-EDTA and stabilizers, such as a cyclodextrin. The amount and type of excipient added is in accordance with the particular requirements and is generally in the range of from approximately 0001 to approximately 90% by weight.
In another embodiment of the present invention, the ophthalmic composition comprises a therapeutically effective amount of alpha 1 antagonist, a carrier, a solubilizer and another therapeutically effective pharmaceutical agent which may be, for example, an antibiotic, an antiallergic, an anesthetic, or another drug.
A range of different alpha 1 antagonists are known to those skilled in the art. The present invention is intended to encompass such compounds and equivalent compounds which have substantially the same therapeutic effect as the present invention. Specifically, the present invention is intended to encompass formulations which comprise an aqueous solvent having dissolved therein a therapeutically effective amount of a compound which compound when dissolved in the formulation in a low concentration (1% or less) and administered to a human patient""s eye will prevent dilation of the eye in dim light to a level which is about twice the amount of dilation or less than occurs when the patient is present in bright light.
As indicated above a simple formulation of the present invention comprises an aqueous solvent which may be sterile water suitable for administration to the eye having an alpha 1 antagonist dissolved therein in a low concentration, e.g. 1% concentration or less. However, preferred formulations of the present invention are comprised of alpha 1 antagonist dissolved in a formulation which is referred to in the art as an artificial tear formulation. Such formulations are disclosed and described within U.S. Pat. No. 5,895,654; 5,627,611; and 5,591,426 as well as patents and publications cited and referred to in these patents, all of which are intended to be incorporated herein by reference.
Artificial tear formulations of the invention promote good wettability and spread. Further, the artificial tear formulations preferably have good retention and stability on the eye and do not cause significant discomfort to the user . A preferred artificial tear composition of the invention, comprises
(1) polyvinylpyrrolidone, preferably in the amount of about 0.1-5% by weight of said solution;
(2) benzalkonium chloride, preferably in an amount of about 0.01-0.10% by weight;
(3) hydroxypropyl methylcellulose, preferably in an amount of about 0.2-1.5% by weight of said solution; and
(4) glycerin, preferably in an amount of about 0.2-1.0% by weight of said solution, wherein the composition is an aqueous solution having isotonic properties.
Those skilled in the art will recognize that a wide range of different formulations and artificial tear formulations which can be utilized in connection with the present invention.
Formulations of the present invention can be administered in accordance with means generally known to those skilled in the art. Generally, the formulation is administered using an eyedropper. The eyedropper may be a conventional eyedropper which is comprised of a hollow cylindrical barrel having a first end and a second end and an inner surface. Further, the eyedropper will be further comprised of a means for providing suction to draw the formulation of the invention into the hollow cylindrical barrel. The first end of the barrel is configured to receive the means for providing suction to draw in a formulation. The second end of the barrel is generally configured to have a small opening which permits passage of the formulation and allows drops of the formulation to be metered out directly onto the patient""s eye. The cylindrical barrel is preferably designed so that it is relatively small and contains less than 5 cubic centimeters of formulation.
It may be desirable to utilize a measured dose eyedropper of the type described within U.S. Pat. No. 5,514,118 or an illuminated eyedropper device of the type described in U.S. Pat. No. 5,584,823. A range of other eye droppers can also be utilized of the type described within the following U.S. Pat. No. 5,059,188; 4,834,727; 4,629,456; and 4,515,295. The patents cited here which disclose eyedroppers are incorporated herein by reference as are the various patents and publications cited and discussed within these patents.

Ophthalmic formulation which modulates dilation